Experimental model of doxorubicin extravasation in the mouse

Abstract

Doxorubicin (Adriamycin), a widely used antitumor agent, can occasionally cause severe and protracted local tissue damage if inadvertently extravasated during intravenous injection. An animal model was developed in adult BALB/c mice to experimentally duplicate such human skin toxicity, Intradermal (ID) doxorubicin injections of 0.5, 0.05 and 0.005 mg (per 0.05 ml) provided reproducible, dose-related skin lesions, quantitated with daily measurement of perpendicular diameters of induration, erythema, and ulceration. Maximal lesions developed rapidly (within 3-5 days) and slowly resolved over 30-40 days. There were dose-related increments in peak toxicity levels, total toxicity, and the duration of damage for each parameter (0.5 > 0.05 > 0.005 mg). Subcutaneous (ie, subpannicular) injections, and ID saline control injections did not cause local skin toxicity. A local intervention with ID hydrocortisone (2.5 mg) substantially reduced erythema and induration, and eliminated ulceration only in animals receiving the lower dose (0.05 mg) doxorubicin challenge (p < 0.05). This direct skin toxicity method is compared to reported animal skin toxicity models, and the intervention results are discussed in reference to current toxicity observations in man.